Alkanolamine derivatives

ABSTRACT

1-O-OXIMINOMETHYLPHENOXY-3-AMINO-2-PROPANOL DERIVATIVES, PROCESSES FOR THEIR MANUFACTURE, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND A METHOD OF USING THEM IN THE TREATMENT OF HEART DISEASE. The compounds possess Beta -adrenergic blocking activity. Representative of the compounds disclosed is o-(2hydroxy-3-t-butylaminopropoxy)-benzaldehyde oxime.

United States Patent Ashby 14 1 Sept. 9, 1975 [541 ALKANOLAMINEDERIVATIVES FOREIGN PATENTS OR APPLICATIONS Inventor! Ernest John Ashby,Macclesfield, 1,231,783 5 1971 United Kingdom 260/566 A England [73]Asslgnee'z fir i g f g g Primary Examin'erGerald A. Schwartz e on ng anAttorney, Agent, or Firm-Cushman, Darby & [22] Filed: May 8, 1973Cushman [2]] Appl. No.2 358,349

57 ABSTRACT [30] Foreign Application Priority Data 1 June 1, 1972 UnitedKingdom 25709/72 1- ximin methylphen0xy-3-arnino-2-propanol deriv- 1atives, processes for their manufacture, pharmaceuti- Cl 260/566 A;260/2.1 E; 2 cal compositions containing them and a method of 260/5424/327 using them in the treatment of heart disease. The com- [51] Int.Cl. C07c 131/00 ounds possess fl-adrenergic blocking activity. Repre'[58] Field of Search 260/566 A, 566 sentative of the compounds disclosedis o-(2-hydroxy- 50 1 17 3-t-butylaminopropoxy )-benzal.dehyde oxime.

[56] References Cited 5 Claims, N0 Drawings UNITED STATES PATENTS I I3,732,277 5/l973 Koppe et a1. 260/566 A X 1 2 ALKANOLAMINE DERIVATIVEStiomorphic forms. At least one, and possibly both, of I theseenantiomorphic forms will possess B-adrenergic This invention relates toimproved alkanolamine blocking activity. It is to be understood,therefore, that rivatives which Possess .Badfenergic blocking activitythis invention encompasses the racemic form of the al- In United Kingdom133L783 there is a general kanolamine derivative and any enantiomorphicform description of a large number of alkanolamine deriva' whichpossesses B-adrene r'gic blocking activity. It is to fives includingcompounds of formula: be understood-that B adrenergic blocking activityusu-' ally priedominates in that enantiomorphic form which Preferablythe alkyl or hydroxyalkyl radical R cori- (Rh tains or 4 carbon atomsand is branched at the or-car .C=NR bon atom. R may be,"for example, the'isio propyl, s

. R"" butyl, t-butyl, 2-hydroxy-l-methylethyl, 2-hydroxy 1,1-

r q dimethylethyl,.cyclopropyl,cyclobutyl, cyclopentyl or wherein R maybe, inter alia, the hydrogen atom; R cyclohexyl l g may mter i E am l Asuitable value for R when it stands for an alkyl propyl or t'butylgFPUP; R may Inter the radical is, for example, the methyl, ethyl orn-propyl drogen atom or an alkyl ,oraryl group; R may be, 0 radicaLinter alia, a group of the formula -OR""', wherein R"" representsthehydrogen atom or an alkyl, aryl or aralkyl group; R maybe a halogenatom or may have various other values and n may be zero or an integerfrom 1 to 4 inclusive, and their acid-addition salts. The

compounds are stated to antagonise some effects of adrenaline,noradrenaline and sympathetic stimulation A Fultable San of analkanolammej on cardiac muscle and show antiarrythmic properties.nvatweof the mvenuon 'foriexample a y' There is no specific example insaid specification of froman 'Q acld, for p a y U any Compound in whichthe substituent is the hydrobromide, phosphate or sulphate, or a saltderived drogen atom The majority f compounds Specifically from anorganic acid, for example an oxalate, lactate, exemplified have forR themethyl group; although taftfate, acetate, a y Citrate, beYIZOate, B- P Asuitable value for R? when it stands for a halogen atom is, for example,the fluorine, chlorine, bromine or iodine atom. The halogen atom R, ifpresent, is preferably in the 4-position of the benzene ring withrespect 25 to the alkanolamine side-chain.

some have a hydrocarbon substituent R' which conthoate, adipate orl,l-methylene-bis-(2-hydroxy-3- tains more than one carbon atom.naphthoate), or a salt derived from an acidic synthetic We have nowfound, and herein lies our invention, resin, for example a sulphonatedpolystyrene resin, for that certain compounds of the type describedabove exampleZeo-Kar b 22 5 (Zeo-Ka'rb is aTrade Mark). wherein R standsfor hydrogen are much more active A specific alkanolamine derivative ofthe invention as B-adrenergic blocking agents (that is, agents which i'f g a l 2 h' d 3sf antagonise certain effects of catecholamines such asi i' i'flifip b w ii id h m b 2. adrenalme) than are the correspondingcompounds, 0 hydroxy-3-tbutylaminopropoxy)-benzaldeliyde oxim'edescribed in the said specification, wherein R' stands or anacid-addition salt thereof. I for the methyl. group Furthermore the-SeThe alkanolamine derivative of the invention maybe pounds wherein R'stands for hydrogen, unlike the f manufactured by any chemical processknown to be corresponding compounds Wherem Stands or h useful for themanufacture of chemically-analogous methyl radical, possesseardro-selectrve ,B-adrenergic d blocking activity as hereinafterdefined Compoun. 1

According to a further feature of the invention there According to theinvention there 18 provided a novel I is provided a process for themanufacture of the alkaalkanolamlne derivative-of the formula: l

v I nolamme derivative of the invention which comprises assembling insequence by chemical synthesis, the five radicals:

i, an oximino radical of the formula:

the meaning stated above for R H=N-O-R n. a phenoxy radical of theformula:

wherein R stands for an alkyl, hydroxyalkyl or cycloalkyl radical eachof up to 6 carbon atoms, wherein R 3 stands for hydrogen or for an alkylradical of up to 6 carbon atoms and wherein R stands forhy'drogen or fora halogen atom, or an acid-addition salt thereof.

It is to be understood that, in addition to possible synandanti-isomerism at the oximino group. the alkanolamine derivative of ,theinvention possesses an asyr n met- I 1 V j ric carbon atom, namely thecarbon atom of the wherein R has the meaning stated above; -CHOH- groupin the alkanolamine side-chain, and iii; an oxygenated three carbonradical of the formula: it may therefore be resolved intooptically-active enant wherein R either stands for a protecting group orhas wherein R stands for hydrogen or for a protecting group;

iv. an imino radical of the formula NR wherein R stands for hydrogen orfor a protecting group; and

v. a radical of the formula R, wherein R has the meaning stated above; I

whereafter if one or more of R, R and R stands for a protecting group,the one or more protecting groups are removed. 7 H The various stages ofthe assembly may be carried out in any possible order. Thus, forexample:

a. a phenol of the formula:

wherein R and R have the meanings stated above, may first be reactedwith an oxygenated three-carbon derivative, for example a compound ofthe formula:

' mula RR NH, wherein R and R have the'meanings OCH- X wherein R and Rhave the meanings stated above and wherein X stands for the group CH-\CH or the group wherein R and Y have the meanings stated above, orwhich may be, when R stands for hydrogen, a mixture of such compoundswherein X has both meanings stated above, is then reacted with an amineof the forstated above, or with a precursor of such an amine. b. Anoxygenated three-carbon derivative, for example a compound of theformula:

wherein R Y and Z have the meanings stated above, is reacted with anamine of the formula RR NH, wherein R and R have the meanings statedabove, or with a precursor of such an amine. lf Z stands for the hydroxyradical the intermediate compound obtained is further reacted with areagent'which will replace the primary hydroxy radical Z with adisplaceable radical Y. The resulting product, which is a compound ofthe formula XCH .NRR, wherein R, R and X have the meanings stated above,or which may be, when R stands for hydrogen, a mixture of such compoundswherein X has both meanings stated above, is then reacted with a phenolof the formula:

wherein R and R have the meanings stated above.

A suitable value for Y, or for Z when it stands for a displaceableradical, .is, for example, a halogen atom, for example, the chlorine orbromine atom, or a sulphonyloxy radical, forexample analkanesulphonyloxy radical of up to 6 carbon atoms or anarenesulphonyloxy radical of up to 10 carbon atoms, for example themethanesulphonyloxy, benzene-sulphonyloxy or toluene-p-sulphonyloxyradical.

A suitable reagent which will replace the primary hydroxy radical Z witha displaceable radical Y is, for example, a halogenating agent, forexample a thionyl halide, for example thionyl chlorideor thionylbromide, or a sulphonylating agent, for example an alkanesulphonylhalide or an arenesulphonyl halide, for example methanesulphonylchloride, benzenesulphonyl chloride or toluene-p-sulphonyl chloride.

The reaction involving a phenol reactant may be carried out in thepresence of an acid-binding agent, for example an alkali metalhydroxide, for example sodium hydroxide, or an organic base, for examplepiperidine. Alternatively, an alkali metal derivative of the phenolreactant, for example the sodium or potassium derivative, may be used asstarting material. The reaction may be carried out in a diluent orsolvent, for example methanol or ethanol, and it may be accelerated orcompleted by the application of heat, for example by heating to theboiling point of the diluent or solvent.

The reaction involving an amine of .the formula RR"NH may be carried outat ambient temperature or it may be accelerated or completed by theapplication of heat, for example by heating to a temperature of l 10C.;it may be carried out at atmospheric or at an elevated pressure, forexample by heating in a sealed vessel; and it may be carried out in aninert diluent or solvent, for example methanol or ethanol, or an excessof the amine of the formula RRNH, wherein R and R have the meaningsstated above, may be used as uent or solvent. I v

A suitable precursor of the amine of the formula RR NH, is, for example,a urea of the formula- RR'N.CO.NRR, wherein R and R have the mean- 5ings stated above. The reaction involving a urea may be carried out in ahigh boiling diluent or solvent, for example tetralin, decalin orbenzonitrile, and it may be carried out at a temperature of between 150and 220C. c. The series of reactions described under (a) or (b) abovemay be carried out except that-a phenol of the formula:

dil-' CH=O wherein R" has the meaning stated above is usedin place ofthe phenol of the formula:

wherein R, R", R and R have the meanings stated above, is then reactedwith a hydroxylamine derivative of the formula:

H N-O--R* I wherein R has the meaning stated above. The reactioninvolving a hydroxylamine maybe carried out in a diluent or solvent, forexample ethanol, and it may be accelerated or completed by theapplication of heat, for example by heating to the boiling point of thediluent or solvent. The reaction is conveniently carried out under basicconditions, forexample in the presence of an alkali metal hydroxide, forexample sodium hydroxide. T

d. The series of reactions described under (a) or (b) or (c) above maybe carried out except'that an amine of the formula RNH is used in placeof an amine of the formula RRNH, it being understood that when R standsfor hydrogen the amine is ammonia. The radical R may then be inserted asa separate step, for example either by the reaction of the final productfrom the series of reactions described under (a) or (b)' or (c') abovewith a compound of the formulaRY, wherein R and Y have the meaningsstated above, or, when R stands for hydrogen, by the reaction underreducing conditions of *the final product from the series of reactionsdescribed under (a) or (b) or (c) above with a carbonyl compound of theformula R .CO.R, wherein R stands for an alkyl radical and R stands foran alkyl or hydroxyalkyl radical, or wherein R and R are joined togetherwith the adjacent carbon atom to form a cycloalkyl radical, such thatthe radical CHR R has the same meaning as is stated above'for R.

A particularly suitable compound of the formula RY is isopropyl bromide.The reaction involving a compound of the formula RY mayconveniently becarried out in the presence of a base, for example sodium or potassiumcarbonate, in a diluent or solvent, for example ethanol or isopropanol,at :an elevated temperature, for example at the boiling point of thediluent or solvent. V z

A particularly suitable compound of the formula R .CO.R is acetone.Suitable: reducing'conditions for the reaction involving the carbonylcompound are those provided by the presence of an alkali metalborohydride, for example sodium borohydride or lithium cyanoborohydride,in an inert diluentor solvent, for example in one or more solventsselected from water, ethanol, methanol and an excess of the carbonyl"co'm pound used as starting material. It is to be understood thatreducing conditions must be chosen such that the oximinomethyl g'rou pCH=NO') is not affected f thereby. e. A compound wherein one or'more ofR, R and R stands for a protecting group may be prepared by the seriesof reactions described under (a) or (b) 'or (c) or (d) above.Alternatively, a suitable protecting group A suitable value for R whenit stands for a protecting group is, for example, an acyl radical asdefined for R or a carbamoyl radical, for example a radical of theformula CONHR, wherein-R has the meaning stated above.

Alternatively, R" and R may be joined together so that one protectinggroup serves to protect both the oxygen and nitrogen atoms. Such aprotecting group may be, for example, the carbonyl -CO) radical, suchthat it forms, together with the adjacent oxygen and nitrogen atoms andtwo carbon atoms of the threecarbon radical, an oxazolidinone nucleus,or it may be a radical of the formula CHIR wherein R" stands forhydrogen, or for an alkyl radical of up to 4 carbon atoms or-an arylradical of up to 10 carbon atoms, such that it forms, together with theadjacent oxygen and ni trogen atoms and two carbonatom s of thethreecarbon radical, an oxazolidine nucleus.

The acyl protecting group R or R, or the.carbamoyl" protecting group R,or the carbonyl protecting-group formed by R and R taken together, maybe removed by hydrolysis in the presence of a base, for example anwherein R and R have the meanings stated above (bothof which compoundsmay be obtainedby the reaction of the corresponding phenol withepichlorohydrin with an amine of the formula RNH wherein R has themeaning stated above.

A second, and more particularly, preferred process for the manufactureof the alkanolamine derivative of the invention comprises the reactionof a compound of the formula;

CHO

wherein R and R have the meanings stated above, with a hydroxylaminederivative of the, formula:

wherein R has the meaning stated above.

Optically-active enantiomorphs of the alkanolamine derivative of theinvention may 'be obtained by the resolution by conventional means ofthe corresponding racemic alkanolamine derivative of the invention.

The said resolution may be carried out by reacting the racemicalkanolamine derivative with an opticallyactive acid, followed byfractional cyrstallisation of the diastereoisomeric mixture of. saltsthus obtained from a diluent or solvent, for example ethanol, whereafterthe optically-active alkanolamine derivative is liberated from thesaltby treatment with a base. A suitable optically-active acid is, forexample, or (-)-0,0-di-p-toluoyl-tartaric acid. 1 l

The resolution process may be facilitated-by treating the partiallyresolved alkanolamine derivative in free base form obtained after asingle fractional crystallisatio'n' ofthe diastereoisomeric mixture ofsalts'with a solubilising agent, for example a primary amine, forexample .allylamine, in .a relatively non-polar diluent or solvent, forexample petroleum ether.

The alkanolamine derivative of the invention in free base form may beconverted into an acid-addition salt thereof by reaction with an acid byconventional means As stated above, the alkanolamine derivative of theinvention or an acid-addition salt thereof possesses cardio-selective,B-adrenergic blocking activity. The B-adrenergic blocking activity maybe determined by reversal of isoprenaline-induced tachycardia in rats orcats, a standard test forthe determination of ,B-adrenergic blockingactivity, and the cardiac selectivity may be demonstrated by relativefreedom from antagonism of isoprenaline-induced vasodilatation in catsor of the relief produced by isoprenaline of histamine-inducedbronchospasm in guinea pigs. Compounds exhibiting this selective actionshow a greater degree of specificity in blocking the cardiac B-receptorsthan the B-receptors in peripheral blood vessels and bronchial muscle.Thus, a dose may be selected for such a compound at which the compoundblocks the cardiac chronotropic action of a catecholamine [for exampleisoprenaline, that is, 1-( 3,4-dihydroxyphenyl )-2-isopropylaminoethanol] but does not block the relaxation of trachealsmooth muscle produced by isoprenaline or the peripheral vasodilatoraction of isoprenaline. Because of this selective action, one of thesecompounds may advantageously be used together with a sympathomimeticbronchodilator, for example isoprenaline, orciprenaline, adrenaline orephedrine, in the treatment of asthma and other obstructive airwaysdiseases, inasmuch as. the selective compound will substantially inhibitthe unwanted stimulatory effects of the bronchodilator on the heart butwill not hinder the desirable therapeutic effect of the bronchodilator.

The advantage of an alkanolamine derivative of the present inventionover the most closely related compound described in United Kingdom No.1,231,783 is exemplified in the following table. The 50%-effectivecardiac B-adrenergic blocking dose (the ED,,,,) is defined as thatamount of alkanolamine derivative, in pig/kg, which when administered toa chloraloseanaesthetised cat during 30 minutes lowers by 50% thetachycardia induced in the cat by a single dose of 0.2 ug/kg. ofisoprenaline. The noncardiac B-adrenergic blocking effect isdemonstrated by the effect on the isoprenalin e-induced fall in bloodpressure of the cat at the ED and this is defined as the SP A negativeor small positive BP figure indicates cardio-selectivity; a BP figure of50 indicates non-cardio-selectivity, that is, the alkanolaminederivative is equally effective in blocking the effect of isoprenalineon the cardiac and peripheral B-receptors. I

Compounds 1 to 3 have the general formula:

compounds 1 andv 2 being alkanolamine derivatives of the presentinvention and Compound 3 being a compound described in United KingdomNo. 1,231,783. Compounds 4 and 5 are respectively practolol, a

Compound No. R R ED -y, BP

1 isopropyl H 25 2 t-butyl H 1 9 +1 3 isopropyl methyl 177 +37 4practolol I67 +8 5 propranolol 62 +85 At doses of an alkanolaminederivative of the invention which produce effective ,B-adrenergicblockade in rats or cats, no symptoms of toxicity are apparent.

The alkanolamine derivative of the invention may be administered towarm-blooded animals, including man, in the form of a pharmaceuticalcomposition comprising as active ingredient at least one alkanolaminederivative of the invention, or an acid-addition salt thereof, inassociation with a pharmaceutically-acceptable diluent or carriertherefor. I

A suitable composition is, for example, a tablet, capsule, aqueous oroily solution or suspension, emulsion, injectable aqueous or oilysolution or suspension, dispersible powder, spray or aerosolformulation.

The pharmaceutical composition may contain, in addition to thealkanolamine derivative of the invention, one or more drugs selectedfrom sedatives, for example phenobarbitone, meprobamate, chlorpromazineand the benzodiazepine sedative drugs, for example chlordiazepoxide anddiazepam; vasodilators, for example glyceryl trinitrate, pentaerythritol'tetranitrate and isosorbide dinitrate; diuretics, for examplechlorothiazide; hypotensive agents, for example reserpine, bethanidineand guanethidine; myocardial depressants, for example quinidine; agentsused in thetreatment of Parkinsons disease, for example benzhexol;cariotonic agents, for example digitalis preparations; andsympathomimetic bronchodilators, for example isoprenaline,orciprenaline, adrenaline and ephedrine.

When used for the treatment of heart diseases, for example anginapectoris and cardiac arrhythmias, or for the treatment of hypertension,in man it is expected that the alkanolamine derivative would be given toman at a total oral dose of between 20 mg. and 600 mg.

daily, at doses spaced at 6-8 hourly intervals, or at an intravenousdose of between 1 mg. and 20 mg. Preferred oral dosage forms are tabletsor capsules containing between 10 and 100 mg., and preferably 10 mg. or40 mg. of active ingredient. Preferred intravenous dosage forms aresterile aqueous solutions of the alkanolamine derivative or of anon-toxic acid-addition salt thereof, containing between 0.05% and 1%w/v of active ingredient, and more particularly containing 0.1% w/v ofactive ingredient.

The invention is illustrated but not limited by the following Examples:

EXAMPLE 1 A solution of hydroxylamine hydrochloride (0.695

g.) in water (5 ml.) is added] to a solution ofl-oformylphenoxy-3-isopropylamino-2-propanol (2.37 g.) in ethanol 10ml.) and aqueous ZN-sodium hydroxide solution is added until the pH ofthe mixture is 10. The mixture is heated under reflux for 2.5 hours andthen poured into water, and the resulting mixture is extracted withmethylene chloride (3 X ml. The extract is dried and evaporated todryness, the residue is dissolved in ethyl acetate and a solution ofoxalic acid in ethyl acetate is added. The mixture is filtered and thereis thus obtained o-( 2-hydroxy-3- isopropylaminopropoxy)-benzaldehydeoxime oxalate, m.p. C.

EXAMPLE 2 The process described in Example 1 is repeated except that l-o-formylphe1noxy-3 -t-butylamino-2- propanol is used as startingmaterial in place of the corresponding isopropylamino compound, and thatthe final product in free-base form is converted to the by drochloridethereof in place of the oxalate. There is thus obtainedo-(2-hydroxy-3-t-butylaminopropoxy)- benzaldehyde'oxime hydrochloride,m.p. l86*l87C. after crystallisation from isopropyl alcohol.

What I claim is: I

1. An alkanolamine derivative selected from compounds of the formula:

wherein R' is alkyl or hydroxyalkyl, each of 3 or 4 carbon atoms whichis branched at the a-carbon atom, or cycloalkyl of .up to 6 carbonatoms, wherein R is hydrogen or alkyl of up to 6 carbon atoms andwherein R is hydrogen or halogen, and the salts thereof orpharmaceutically acceptable acids.

2. An alkanolamine derivative as claimed in claim 1 selected fromcompounds of the formula given in claim 1 wherein R is isopropyl,s-butyl, t-butyl, 2-hydroxy-lmethylethyl, 2-hydroxyl l -dimethylethyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein R ishydrogen, methyl, ethyl or n-propyl, and wherein R is hydrogen,fluorine, chlorine, bromine or iodine, and the acid-addition saltsthereof.

3. The compound claimed in claim 1 which is o-(2-hydroxy-3-isopropylaminopropoxy)benzaldehyde oxime or an acid-additionsalt thereof.

4. The compound claimed in claim 1 which is o-(2-hydroxy-3-t-butylaminopropoxy)benzaldehyde oxime or an acid-additionsaltthereof.

5. An acid-addition salt as claimed in claim 1 which is a hydrochloride,hydrobromide, phosphate, sulphate, oxalate, lactate, tartrate, acetate,salicylate, citrate, benzoate, B-naphthoate, adipate orl,lmethylene-bis- (2-hydroxy-3-naphthoate

1. AN ALKANOLAMINE DERIVATIVE SELECTED FROM THE COMPOUNDS OF THEFORMULA:
 2. An alkanolamine derivative as claimed in claim 1 selectedfrom compounds of the formula given in claim 1 wherein R1 is isopropyl,s-butyl, t-butyl, 2-hydroxy-1-methylethyl, 2-hydroxy-1,1-dimethylethyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein R2 ishydrogen, methyl, ethyl or n-propyl, and wherein R3 is hydrogen,fluorine, chlorine, bromine or iodine, and the acid-addition saltsthereof.
 3. The compound claimed in claim 1 which iso-(2-hydroxy-3-isopropylaminopropoxy)benzaldehyde oxime or anacid-addition salt thereof.
 4. The compound claimed in claim 1 which iso-(2-hydroxy-3-t-butylaminopropoxy)benzaldehyde oxime or anacid-addition salt thereof.
 5. An acid-addition salt as claimed in claim1 which is a hydrochloride, hydrobromide, phosphate, sulphate, oxalate,lactate, tartrate, acetate, salicylate, citrate, benzoate, Beta-naphthoate, adipate or 1,1-methylene-bis-(2-hydroxy-3-naphthoate).